1. Field of the Invention
The present invention relates to a novel, essentially enantiomerically pure diarylmethylpiperazine compound having utility as a receptor-binding species, e.g., as a mu and/or delta receptor opioid compound mediating analgesia; as a therapeutic agent for co-administration with various other bioactive compositions, including anesthetics, barbiturates, analgesics, etc. for reducing, treating, reversing or preventing drug-mediated respiratory depression that may be directly or indirectly caused by use of such various bioactive compositions; as a conjugate in agonist/antagonist pairing for verifying/assaying receptor and neurotransmitter function; and as a therapeutic agent having utility in combating drug addiction, alcohol addiction, cardiac disorders, drug overdose, mental illness, cough, lung edema, diarrhea, respiratory, and gastro-intestinal disorders.
2. Description of Related Art
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors.
Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (μ), delta (δ), sigma (σ) and kappa (κ) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit; kappa receptors mediate analgesia and sedation: and sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a relatively recent discovery which followed the isolation and characterization of endogenous enkephalin peptides which are ligands for the delta receptor. Research in the past decade has produced significant information about the delta receptor. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Opioid agents frequently are characterized as either agonists or antagonists. Agonists and antagonists are agents which recognize and bind to receptors, affecting (either initiating or blocking) biochemical/physiological sequences, a process known as transduction. Agonists inhibit or suppress neurotransmitter outputs in tissues containing receptors, e.g., inhibiting pain responses, or affecting other output-related phenomena. Antagonists also bind to receptors, but do not inhibit neurotransmitter outputs. Thus, antagonists bind to the receptor sites and block the binding of agonist species which are selective for the same receptor.
Opioid diarylmethylpiperazines having both mu and delta receptor activity have been described in U.S. Pat. No. 5,658,908 (Chang et al.). However, the synthesis of these compounds in the laboratory, having at least one asymmetric carbon atom, invariably leads to a racemic mixture exhibiting no optical activity. In contrast, naturally occurring compounds which possess an asymmetric carbon atom almost invariably are optically active.
In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (−) or d and l are employed to designate the direction of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
For a given chemical structure, different optically active compounds are called stereoisomers and are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where many of the most prescribed drugs exhibit chirality. An illustrative example is the l-form of propranolol, which is known to be 100 times more potent than the d-enantiomer. Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the d-enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy and that the corresponding l-enantiomer is a potent teratogen.
Whereas the foregoing Chang et al. patent recognized that diarylmethylpiperazines may have optically active forms and individual enantiomeric forms may be synthesized, no example of the presently claimed optically active form was given. Although it was generally concluded heretofore that the described diarylmethylpiperazines racemic mixtures and inclusive enantiomers exhibited similar activity, it has been discovered by the present inventors that there are substantial unforeseen advantages in the use of an enantiomerically pure diarylmethylpiperazine of the present invention.